Dexamethasone as an Effective Therapy for Ocular Injuries by Vesicating Agents.

地塞米松是治疗眼部损伤的有效疗法。

基本信息

批准号：
10472580
负责人：
Rajesh Agarwal
金额：
$ 71.47万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10472580
关键词：
Address Adverse effects Arsenicals Blindness Chemical Weapons Clinical Colorado Cornea Corneal Injury Data Development Dexamethasone Dose Drug Prescriptions Evaluation Exposure to Eye Eye Injuries FDA approved Female Food, Drug and Cosmetic Act Frequencies Functional disorder Gelatinase B Human Inflammation Inflammation Mediators Injury Intellectual Property Lead Licensure Mechlorethamine Medical emergency Modeling Molecular Mustard Mustard Gas Organ Organ Culture Techniques Oryctolagus cuniculus PTGS2 gene Pathway interactions Pharmaceutical Preparations Positioning Attribute Process Regulatory Pathway Reporting Research Safety Sampling Studies Source Suggestion Technology Transfer Therapeutic Therapeutic Agents Time Tissues Topical Preparation Toxic effect Treatment Protocols Universities Vascular Endothelial Growth Factors Vesicants analog base cost drug development effective therapy efficacy study gender difference in vivo in vivo Model innovation lead optimization lewisite limbal male mass casualty neovascularization stem cells targeted treatment therapeutic target

项目摘要

Project Summary Abstract Sulfur mustard (SM), nitrogen mustard (NM) and lewisite (LEW) are vesicating agents that are among the most potent chemical weapons, and are the current focus for the development of countermeasures. In the past, lack of NM-, SM- and LEW-induced ocular injury models to identify the mechanisms of toxicity and therapeutic targets has been a major impediment to developing effective therapies. However, in recent years, we have successfully developed and characterized all three vesicants (NM, SM, and LEW)-induced ocular (corneal) injury models in vivo in rabbits, relevant to humans. Also, we identified an increased expression of COX-2 and iNOS, VEGF, and MMP-9 as possible mediators of inflammation, neovascularization (NV) and microvesication, respectively, in ocular injuries by these three vesicants. This is an important finding as it suggests that an agent effective against the ocular injury induced by one of these vesicants would also be effective against the others. Indeed, in our proof of concept efficacy studies, we demonstrated that dexamethasone (DEX, an FDA approved drug) is an effective agent in ameliorating all three vesicants (NM, SM, LEW)-induced ocular injuries in vivo in rabbits. This is a significant finding because the regulatory pathway for this new use of DEX is much easier to pursue, since the new use application for DEX would be able to rely on the existing safety and efficacy data of the reference DEX application, leading to less data needed for the application and an easier approval pathway. An advantage of DEX, based on review by the CU technology transfer office, is that there are no competitive intellectual property (IP) barriers to bringing this new use to market. The further advantage of using DEX is that we do not need to generate additional IP in order to create a commercial product, as DEX is available at a low cost from multiple sources as a generic and branded prescription drug, and will have no shortages in times of a medical emergency. Together, based on our completed studies and clear regulatory pathway forward, our hypothesis is that DEX has strong potential to reverse both mustard- and arsenical-induced ocular injury, and that as a promising targeted `optimized lead' therapeutic, it can be easily available for human use in medical emergency. Our specific aims are to: 1) optimize dosing frequency of DEX to treat vesicating agents-induced in vivo ocular injury in rabbits; 2) evaluate the most effective DEX treatment regimen to counteract vesicating agents-induced corneal injury in human corneal organ culture; 3) define the molecular mechanism of DEX in rescuing vesicating agents-induced ocular injury; and 4) develop and follow regulatory strategies for approval of DEX indication as an effective countermeasure against vesicating agent-induced ocular injury. Completion of our aims is anticipated to make dexamethasone ready for next stage of advanced drug development process with a clear path for FDA approval as an effective rescue medication for vesicants-induced ocular injuries.

项目概要摘要硫芥 (SM)、氮芥 (NM) 和路易斯 (LEW) 是最常用的发泡剂。强效化学武器，是当前制定对策的重点。过去，缺乏 NM、SM 和 LEW 诱导的眼损伤模型以确定毒性和治疗机制目标一直是开发有效疗法的主要障碍。然而，近年来，我们成功开发并表征了所有三种起泡剂（NM、SM 和 LEW）诱导的眼部（角膜）与人类相关的兔子体内损伤模型。此外，我们还发现 COX-2 的表达增加， iNOS、VEGF 和 MMP-9 作为炎症、新生血管形成 (NV) 和微泡化的可能介质，分别在这三种出疱剂造成的眼部损伤中。这是一个重要的发现，因为它表明有效对抗由这些起泡剂之一引起的眼损伤的药剂也将有效对抗其他的。事实上，在我们的概念验证功效研究中，我们证明了地塞米松（DEX，一种 FDA 批准的药物）是改善所有三种出疱剂（NM、SM、LEW）引起的有效药物兔体内眼部损伤。这是一个重大发现，因为这种新用途的监管途径 DEX 的使用更容易实现，因为 DEX 的新使用申请将能够依赖现有的参考 DEX 应用程序的安全性和有效性数据，从而减少应用程序所需的数据，并且更简单的审批途径。根据CU技术转让办公室的审查，DEX的一个优势是将这种新用途推向市场不存在竞争性知识产权（IP）障碍。进一步的使用DEX的优点是我们不需要生成额外的IP来创建商业产品，因为 DEX 作为仿制药和品牌处方药可以从多个来源以低成本获得，并且在发生医疗紧急情况时不会出现短缺。一起，基于我们完成的研究和明确的监管路径，我们的假设是 DEX 有强大的潜力扭转这两种局面芥末和砷引起的眼损伤，作为一种有前途的靶向“优化先导” 治疗，它可以很容易地供人类在医疗紧急情况下使用。我们的具体目标是：1) 优化 DEX 的给药频率，以治疗起泡剂引起的家兔体内眼损伤； 2）评估对抗起泡剂引起的人类角膜损伤最有效的 DEX 治疗方案角膜器官培养； 3) 明确DEX拯救水泡剂引起的眼病的分子机制受伤; 4) 制定并遵循监管策略，批准 DEX 指示作为有效的对抗起泡剂引起的眼损伤的对策。预计完成我们的目标使地塞米松为下一阶段的先进药物开发过程做好准备，并提供明确的路径 FDA 批准作为治疗起泡剂引起的眼损伤的有效救援药物。